Preferential CEBP binding to T:G mismatches and increased C-to-T human somatic mutations

Nucleic Acids Res. 2021 May 21;49(9):5084-5094. doi: 10.1093/nar/gkab276.


DNA cytosine methylation in mammals modulates gene expression and chromatin accessibility. It also impacts mutation rates, via spontaneous oxidative deamination of 5-methylcytosine (5mC) to thymine. In most cases the resulting T:G mismatches are repaired, following T excision by one of the thymine DNA glycosylases, TDG or MBD4. We found that C-to-T mutations are enriched in the binding sites of CCAAT/enhancer binding proteins (CEBP). Within a CEBP site, the presence of a T:G mismatch increased CEBPβ binding affinity by a factor of >60 relative to the normal C:G base pair. This enhanced binding to a mismatch inhibits its repair by both TDG and MBD4 in vitro. Furthermore, repair of the deamination product of unmethylated cytosine, which yields a U:G DNA mismatch that is normally repaired via uracil DNA glycosylase, is also inhibited by CEBPβ binding. Passage of a replication fork over either a T:G or U:G mismatch, before repair can occur, results in a C-to-T mutation in one of the daughter duplexes. Our study thus provides a plausible mechanism for accumulation of C-to-T human somatic mutations.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Base Pair Mismatch*
  • Binding Sites
  • CCAAT-Enhancer-Binding Proteins / chemistry
  • CCAAT-Enhancer-Binding Proteins / metabolism*
  • Cytosine / chemistry
  • DNA / chemistry
  • DNA / metabolism
  • DNA Repair
  • Guanine / chemistry
  • Humans
  • Mutation
  • Protein Binding
  • Protein Domains
  • Thymine / chemistry


  • CCAAT-Enhancer-Binding Proteins
  • Guanine
  • Cytosine
  • DNA
  • Thymine